This grant proposal introduces a new concept for an implantable biohybrid artificial pancreas to treat Type I Diabetes Mellitus. Among the many limited approaches attempted, the most successful data has been obtained with transplantation of immunoprotected pancreatic islets. Recognizing the limited life span of islet cells due to an abnormal living environment or in emergency, such as unexpected cell lysis, it will be necessary for the implanted to be retrieved or replaced with fresh islets. Existing systems, such as intraperitoneal grafting of encapsulated islets or intravascular grafting of islets in a housing may have severe limitations for retrieval or replacement. The proposed system consists of an islet/thermosensitive polymer matrix and an immuno-protecting membrane pouch. The thermosensitive polymer matrix undergoes phase transition from a soluble form to a precipitation when the temperature is raised beyond the lower critical solution temperature of the polymer. This allows for the injection and removal of islet suspension in the polymer solution at low temperature and solidifying around islets in the loosely structured polymer matrix at body temperature. This polymer matrix will prevent islets from aggregation in the pouch, will allow efficient diffusion of nutrients, glucose and insulin, and provide an easy method for replacement/retrieval. In addition, this grant proposes to graft sulfonylurea molecules onto thermosensitive polymer chains. This biospecific polymer will stimulate insulin secretion of beta-cells and enhance glucose response. This may offer an opportunity to minimize the number of islets implanted, thereby reducing the implant volume and increase the overall efficiency of the system. The aim of this proposal is to construct a refillable islet/polymer matrix system in a pouch, test its feasibility and optimize the system.